In a normal immune response, T cells are activated by a first, antigen specific, signal which stimulates T cells via the T cell antigen receptor and confers antigen specificity to the immune response; and a second, costimulatory, signal delivered by costimulatory molecules found on the surface of antigen presenting cells. Both signals are required to induce T cell proliferation. If the second costimulatory signal does not occur, or if the co-stimulation pathway is blocked or downregulated, activation of T cells will be reduced or eliminated. This results in hyporesponsiveness of the T cells to antigen and can induce a state of T cell anergy, or T cell nonresponsiveness, wherein the T cells will not proliferate when presented with antigen.
The best characterized co-stimulatory molecules on antigen-presenting cells are the structurally related glycoproteins B7-1 (CD80) and B7-2 (CD86). These are homodimeric members of the immunoglobulin superfamily found exclusively on the surface of cells capable of stimulating T-cell growth. The receptor for B7 molecules on the T-cell is CD28, another member of the immunoglobulin superfamily. Ligation of CD28 by B7-1 or B7-2 or by anti-CD28 antibodies will co-stimulate the growth of naive T-cells, while antibodies to the B7 molecules, which inhibit B7 binding to CD28, inhibit T-cell responses.
The function of the immune system is to eliminate foreign cells that may contain pathogens, while maintaining unresponsiveness or tolerance against self-antigens. Tolerance is manifested by T cell anergy, characterized by the survival, but nonresponsiveness of T cells. However, the immune system may attack self-constituents, causing autoimmune disease. Autoimmune diseases are believed to originate in the abnormal immune response to self-antigens, either due to a change in self-antigens or exposure to crossreactive antigens. Autoimmune diseases caused by antibody-mediated immune responses to self-antigens include diseases such as rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease.
It is desirable to improve present treatments of autoimmune disease or other undesirable immune reactions which use general immunosuppressive agents such as corticosteroids, azathioprine, or cyclosporine A. These treatments are nonselective and do not distinguish between normal and abnormal immune responses. These drugs often have adverse side effects, including general suppression of the immune system with risks of infection and neoplasia, as well as the development of diseases such as diabetes, osteoporosis, leukopenia and hypertension.
Accordingly, in certain circumstances, such as autoimmune disease, a particular immune response may not be desired. Alternative approaches for treatment of these conditions are needed for patients who cannot withstand, or do not respond to, conventional chronic, non-specific drug therapy.
It has been discovered that human mesenchymal stem cells can be used to deliver antigens to the immune system such that an immune response to the antigen will be inhibited, i.e. eliminated, reduced or ameliorated. The reduction or elimination of an immune response by mesenchymal stem cells as described herein can be used as a method to ameliorate an immune response in a recipient against autoimmune disease.
Accordingly the methods of the present invention are particularly useful for eliminating, reducing or ameliorating unwanted or abnormal T cell immune responses. In one aspect the method involves administering to an animal mesenchymal stem cells which have been modified to carry an antigen. Presentation of the antigen to the T cell in the absence of a costimulatory signal induces an antigen-specific state of hyporesponsiveness, or even nonresponsiveness or anergy in the T cell to subsequent challenge to the T cell by the antigen. Thus, an immune response is reduced or eliminated. The elimination, reduction or amelioration of an immune response as described herein can be used as a method to treat or inhibit an unwanted or abnormal immune response such as occurs in autoimmune disease.
In another aspect of the present invention mesenchymal stem cells can be used to present to the immune system molecules that block costimulation pathways which are required to effect an immune response. The elimination, reduction or amelioration of an immune response as described herein can be used as a method to treat or inhibit an unwanted or abnormal immune response such as occurs in autoimmune disease. Blocking the costimulatory signal inhibits T cell activation by antigen specific signals presented by antigen presenting cells that may be in the proximity of the T cells.
In a still further aspect of the invention, the mesenchymal stem cells are used to deliver to the T cells an antigen and a molecule that inhibits the delivery of a costimulation signal to the T cells. Delivering a specific antigen to target T cells in conjunction with blocking the costimulatory signal inhibits specific T cell activation in the presence of antigen specific signal presented by the antigen-presenting mesenchymal stem cell. In a preferred embodiment, molecules that block T cell costimulation are selected from cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or CTLA-4Ig, a fusion protein of CTLA-4 and the constant region of human IgG-1.